Is SETBP1 p.Pro1255Ser (c.3763C>T) pathogenic?

SETBP1 p.Pro1255Ser (c.3763C>T) is classified Conflicting classifications of pathogenicity in SETBP1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-21). AlphaMissense: likely benign (0.0675); Very rare (popmax 0.005%, amr); Associated with SETBP1-related disorder.

What condition is associated with SETBP1 p.Pro1255Ser (c.3763C>T)?

SETBP1 p.Pro1255Ser (c.3763C>T) is associated with SETBP1-related disorder (ClinVar).

How common is SETBP1 p.Pro1255Ser (c.3763C>T) in the general population?

SETBP1 p.Pro1255Ser (c.3763C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about SETBP1 p.Pro1255Ser (c.3763C>T)?

AlphaMissense predicts likely benign (score 0.0675) — an in-silico prediction, not a clinical call.

SETBP1 p.Pro1255Ser

c.3763C>T · rs1386383075 · VCV2197158

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0675 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SETBP1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0675	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -5.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP 0.016, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 110 kb · p 0.16 · regional, not allelic
Overall
CADD	15.91	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,000 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,614,014 alleles · very rare exomes 2/1,461,882 · genomes 1/152,132 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SETBP1
Protein: p.Pro1255Ser
Coding: c.3763C>T
MANE Select: NM_015559
dbSNP: rs1386383075
Type: single nucleotide variant
Location: chr18:44953103 (GRCh38)
Gene constraint: LOEUF 0.143 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.30
Residue 1255: the 'disordered' region

Full SETBP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SETBP1-related disorder

Similar variants

SETBP1 p.Arg544Ter Pathogenic/Likely pathogenic ★★ same condition
SETBP1 p.Arg626Ter Pathogenic ★★ same condition
SETBP1 p.Asp868Asn Pathogenic ★★ ⚠ same condition
SETBP1 p.Ser867Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
SETBP1 p.Lys664Glu Uncertain significance ★★ ⚠ same condition
SETBP1 p.Gln712Ter Pathogenic ★ same condition
SETBP1 p.Pro855Ser Likely pathogenic ★ ⚠ same condition
SETBP1 p.Ser477Ter Pathogenic ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/setbp1-p-pro1255ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown